Abstract: FR-PO970
Pharmacological Inhibition of Lysine-Specific Histone Demethylase 1 With GSK-LSD1 Ameliorates Renal Fibrosis
Session Information
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Jiao, Baihai, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Du, Hao, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Tran, Melanie, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Song, Bo, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Wang, Yanlin, University of Connecticut School of Medicine, Farmington, Connecticut, United States
Background
Renal fibrosis is a pathological hallmark of chronic kidney disease (CKD) which is characterized by tubular epithelial cell dedifferentiation, fibroblast activation, and excessive production and deposition of extracellular matrix resulting in progressive loss of kidney function. However, the molecular mechanisms of renal fibrosis are not fully elucidated. In this study, we investigated the role of lysine-specific histone demethylase 1 (LSD1) in the regulation of tubular epithelial cell dedifferentiation and fibroblast activation during the development of CKD.
Methods
To examine the role of LSD1 in renal fibrosis in vivo, wild-type (WT) mice were subjected to unilateral ureteral obstruction (UUO) and treated with a selective LSD1 inhibitor GSK-LSD1 or vehicle for 10 days. Cultured tubular epithelial cells and fibroblasts were used to examine the role of LSD1 in the regulation of tubular epithelial cell dedifferentiation and fibroblast activation in vitro respectively.
Results
The expression of LSD1 was increased in tubular epithelial cells and myofibroblasts of the UUO kidneys and human kidneys with CKD. Compared with vehicle-treated mice, pharmacological inhibition of LSD1 with GSK-LSD1 significantly repressed UUO-induced histone H3K4 demethylation and Smad3 phosphorylation, reduced tubular epithelial cell dedifferentiation, suppressed myofibroblasts accumulation, and attenuated total collagen deposition and extracellular matrix protein production in the kidneys in response to UUO. Furthermore, pharmacological inhibition of LSD1 with GSK-LSD1 or genetic knockdown of LSD1 with sgRNA eliminates tubular epithelial cell dedifferentiation and fibroblast activation, which is associated with decreased histone H3K4 demethylation and Smad3 phosphorylation.
Conclusion
Our study identifies LSD1 as a critical factor in tubular epithelial cell dedifferentiation, fibroblast activation, and kidney fibrosis through regulation of histone H3 methylation and Smad3 phosphorylation. Therefore, LSD1 may represent a novel therapeutic target for chronic kidney disease.
Funding
- NIDDK Support